Multidrug resistance is now emerging at an alarming rate worldwide. The rise of antibiotic-resistant bacterial strains represents a serious threat to public health and the economy. The severity of this menace is amplified by the fact that research for new antibiotic agents is currently stalled. It may be possible that no new agent active against multidrug resistant bacteria will be put on the market in a close future. The 20th century was the “century of antibiotics”, marked by the discovery and the continuous development of new more and more active antibiotics, but no new antibiotic family has been available for clinicians since 1987. In a world with few effective antibiotics, modern medical advances such as intensive care, transplant and chemotherapy (cancer treatment) may no longer be possible due to the threat of untreatable infections.
Most of the public bodies such as the World Health Organization (2014), the UK Government (2014), the Center for Disease Control and Prevention in the USA (2013) and the Davos Economic Forum in Switzerland (since 2013) have pull the alarm signal to try to control this complex health issue. It is estimated that 25,000 patients die each year in Europe due to multidrug resistance.
As underlined by the latest and important report from the White House in the US (September 2014, National Strategy for Combating Antibiotic Resistant Bacteria) a multiple facet approach is needed. Basically, this strategy is intended to reach four synergistic goals (i) antibiotic stewardship from agriculture to human medicine, (ii) surveying emerged and emerging resistance determinants (iii) accelerate basic and applied research and the development for new antibiotics, other therapeutics and vaccines, (iv) and advance development and use of rapid and innovative diagnostic tests for identification and characterization of resistant bacteria.
Infections are mostly due to either Gram positives such as Staphyloccus aureus and Gram negatives such as Escherichia coli. Most of the important resistance issues are now in emerging Gram negatives (lack of novel anti-Gram negatives agents). They are the main causes of infections in humans. They are the source of both community-acquired and hospital-acquired infections (urinary tract infections, septicemia, intra-abdominal infections . . . ). By far, clinically-significant Gram negatives are the Enterobacteriaceae (E. coli, Klebsiella pneumoniae, Salmonella . . . ).
Urinary tract infections (UTIs) are the most prevalent bacteria-related infectious diseases in humans, with an estimated overall incidence of 18/1,000 persons per year in the United State. According to the Centers for Disease Control and Prevention, UTIs that are mostly due to Escherichia coli (75%) account for more than 8.6 million visits to health care professionals each year in the United States. In addition, multidrug resistance is now emerging worldwide among Gram-negative organisms, which are mostly responsible for UTIs.
A very common resistance trait in Gram-negative bacteria is associated to resistance at least to amino-penicillins due the production of narrow- to broad-spectrum-ß-lactamases. Those enzymes hydrolyze at least aminopenicillins. Resistance to aminopenicillins is observed in 40-80% of E. coli isolates worldwide depending of the geographic area
The ß-lactamases are commonly classified according to two different general schemes; the Ambler molecular classification and the Bush-Jacoby-Medeiros functional classification. The Ambler scheme classifies ß-lactamases into four classes according to the protein homology of enzymes, ß-lactamases of class A, C and D are serine-ß-lactamases and class B enzymes are metallo ß-lactamases. The second classification is the Bush-Jacoby-Medeiros functional scheme based on functional properties of the enzymes. The term “extended-spectrum ß-lactamases” (ESBLs) was originally applied to the TEM and SHV derivatives that can hydrolyze oxyiminocephalosporins being classified in the group 2be with the Bush-Jacoby-Medeiros functional schemes in the 1980's. Those enzymes belong to the Ambler class A group of ß-lactamases and their activity is inhibited by class A inhibitors such as tazobactam, clavulanic acid and sulbactam. More than 700 distinct ß-lactamases have been described, many of them hydrolyzing extended-spectrum cephalosporins and belonging to different types of Ambler groups of enzymes. All ß-lactamases hydrolyze at least amino-penicillins such as amoxicillin.
Resistance to aminopenicillins in Enterobacteriaceae is mostly due to naturally produced narrow-spectrum ß-lactamases such as SHV enzymes in K. pneumoniae or AmpC enzymes in Enterobacter sp, Serratia sp. or to acquired narrow-spectrum class A or class D enzymes such as TEM-1, TEM-2, SHV-1 or OXA-1 enzymes.
One of the most important emerging resistance traits corresponds to resistance to broad-spectrum β-lactams in Enterobacteriaceae, that is mainly associated with extended-spectrum ß-lactamases, i.e ESBLs are of the CTX-M type. It is observed in 5 to 80% of E. coli isolates worldwide. Hence, ESBL-E are usually resistant to most β-lactams including amoxicillin, cefotxime, ceftazidime, except cefoxitin and carbapenems. Therefore, efficient treatment of those infections is becoming challenging due to a concomitant and rapid increase of the prevalence rate of ESBL-E worldwide and the perspective of a paucity of novel anti-Gram-negative molecules. Use of a rapid detection technique to evidence aminopenicillin susceptibility or resistance may significantly contribute to save the efficacy of more broad-spectrum antibiotics of the ß-lactam family as well as other antibiotic families such as fluoroquinolones and aminoglycosides for treating in particularly those infections due to ESBL producers.
WO 2013/072494 discloses a method for detecting the presence of expanded spectrum β-lactamase (ESBLs) producing bacteria in a sample. While this test is useful for specifically detecting the presence of ESBL activity, it does not allow determining whether an infected patient can be successfully treated with an aminopenicillin. As indicated above, 20-60% of E. coli isolates are not resistant to aminopenicillins. In order to reduce the non-adequate or irresponsible use of broad-spectrum antibiotics, it would be advantageous to treat infections due to penicillin-sensitive bacteria with a narrow spectrum penicillin.
It is thus a goal of the invention to reduce the occurrence of resistance to the few broad-spectrum antibiotics that are currently still effective to treat infections due to ESBL producers. This objective is addressed by designing a technique for rapid identification of susceptibility or resistance to aminopenicillins directly from urines or from blood cultures.
The invention is a support for prescription of narrow-spectrum penicillins to treat of UTIs and blood infections due to bacteria that do not possess a narrow or a broad-spectrum-ß-lactamase.
It is in particular a more global goal of the invention to treat UTIs and other infections with penicillins whenever this is possible, such as in the case of those 20-60% of E. coli UTIs, which are not characterized by resistance to penicillins, such as aminopenicillins.
The result of the approach of the invention would be that the use of the currently very few effective broad-spectrum antibiotics is reduced and, as a consequence, the efficacy of those antibiotics can be maintained.
The invention is in particular based also on the notion that the non-adequate or irresponsible use of antibiotics is a key factor for the emergence of resistance to antibiotics. The invention addresses this problem by providing a possibility of using penicillins in the treatment of UTIs and other infections whenever a positive treatment outcome can be anticipated.
The present invention addresses the problems depicted above.